Laser photocoagulator with fluence adaptation

ABSTRACT

The invention concerns a laser photocoagulator comprising a laser emitting at a wavelength within the ICG absorption spectrum and provided with focusing means and a programmed or controlled module powering the laser such that the mean fluence (F) at the focus starting from an initial time varies according to an increasing function in time not varying at any time by more than 10% of an increasing monoexponential corresponding to formula F-F0(1-e-t/r) wherein F is the initial fluence and tau is a time constant ranging between 3 and 5 mn.

The invention relates to apparatus and methods for photocoagulatingtissue, reinforced by administering a chromophore; in general, thechromophore is indocyanine green (ICG) which has an absorption peak inblood at 800 nanometers (nm) and lying in the range 760 nm to 840 nm asa function of dosage. This is the wavelength at whichpresently-available diode lasers emit.

Such methods have already been proposed for destroying neo vessels (newblood vessels) under the retina (article by David R. Guyer et al.“Indocyanine green angiography and dye-enhanced diode laserphotocoagulation”, Seminars in Ophthalmology, Vol. 7, No. 3, 1992) andin dermatology for photocoagulating cutaneous angiodysplasias situatedat depth and difficult to access for treatment by lasers emitting in theabsorption spectrum of hemoglobin.

The use of ICG for photocoagulation nevertheless encounters numerousdifficulties, of which the main difficulty is its short lifetime inplasma, to which there can be added its progressive diffusion away fromthe new vessels into which it has been injected. The use of continuousinjection for compensating short lifetime reduces selectivity because ofthe diffusion.

The invention seeks to reduce the consequences of short lifetime byusing the observation that the dynamics of ICG elimination can bemodelled with an approximation that is satisfactory for a period ofabout 10 minutes after administration in the form of a decreasingmono-exponential function having a time constant that lies in practicein the range 3 minutes (min) to 5 min.

Consequently, the invention proposes a laser photocoagulator comprising:

a laser emitting at a wavelength lying in the absorption spectrum of ICGand provided with focusing means; and

a laser power supply module programmed or controlled so that the meanflux density F at the focus starting from an initial instant varies asan increasing function of time that never departs by more than 10% froman increasing mono-exponential having the form F=F₀(1−e^(−t/τ)) where Fis the initial flux density and τ is a time constant lying in the range3 min to 5 min.

Time t is measured from the administration of ICG and not from thebeginning of laser treatment. F₀ is selected to have a value that is ashigh as possible within the limit set by ensuring selectivity of actionon the vessels that have received the ICG. The present initial F₀ isselected as a function of the injected dose of ICG and of the timeinterval that elapses between injection and the first laser shot on thevessels. In practice, the injected dose of ICG will not exceed about 15milligrams per kilogram (mg/kg) of tissue. The corresponding initialflux density is a decreasing and substantially linear function of dosestarting from an initial value, for a zero dose, of the order of 300joules per square centimeter (J/cm²) for a zero dose.

Varying fluence (flux density) over time makes it possible to causereproducible thermal damage to occur from one operation to another andto conserve selective photocoagulation of those vessels which havereceived ICG, providing that not more than about 10 minutes is allowedto elapse from injection.

The administered power, and thus the fluence, is adjusted by acting onan available parameter of the laser used. In the common case of a pulselaser, the modulus is programmed or controlled to cause the flux densityto vary by modifying unit power and/or duration. The frequency ofsuccessive shots in a sequence can also be adjustable.

For example, it can be stated that a diode laser emitting at 810 nm anddelivering a power of 0.8 watts (W) with pulses being applied over aperiod of up to 10 seconds (s) during which flux density can be variedfrom 60 J/cm² to 360 J/cm² gives good results when destroying vessels inthe dermis.

Ordinary laser photocoagulators generally have an external connectorenabling duration, spacing, and power of pulses to be controlled from anexternal control module. Such a module can include, in particular, aprocessor having a memory containing a program that determines how thepower delivered by the laser photocoagulator should vary over time. Theinvention also provides such a control module programmed so as to causeflux density to vary in application of the above-defined function, and aprogram which, when loaded into a control module, causes said functionto be executed.

In a variant embodiment of the invention, the photocoagulator device isassociated with means that continuously supply an estimate of theconcentration of ICG in the blood, and it is programmed in such a manneras to adjust mean flux density continuously as a function of theestimate so as to achieve compensation. The concentration estimatingmeans can be used for continuously adjusting flux density by correctingthe law stored in the power supply module. These means can also replacethe stored relationship. Finally, they can be used for adjusting thetime constant τ.

By way of example, these means can be constituted by apparatus formeasuring ICG concentration and sold under the name “ICG ClearanceMeter” by Daiichi Pharmaceutical Co., where the estimate ofconcentration is based on the absorption of infrared light by theterminal phalaux of a finger. Such apparatus is used at present only fordetermining the rate at which ICG is eliminated by the liver and thusfor evaluating possible deterioration of liver function.

It is also important to observe that the problem to be solved isassociated with the rapid rate of decrease in the concentration in theblood of a chromophore, in particular ICG, that is injected to enablephotocoagulation by thermal action, and is not associated with the facttumor cells eliminate a photosensitizing agent more quickly than healthycells during laser treatment of a cancer.

The above characteristics and others will appear more clearly on readingthe following description of a particular embodiment, given as anon-limiting example. The description refers to the accompanyingdrawing, in which:

FIG. 1 is a diagram showing the various components of a photocoagulatorwhich can be used for implementing the invention;

FIG. 2 shows an example of how flux density varies as a function of timefrom injection of ICG, for elimination dynamics modelled using adecreasing mono-exponential function with a time constant τ of 4.8 min;and

FIG. 3 is a flow chart for controlling a photocoagulator in a particularimplementation.

The photocoagulator whose general structure is shown by way of examplein FIG. 1 comprises an assembly 10 containing a laser diode and itspower supply module in a housing having a front panel provided withcontrol buttons and indicators making it possible to adjust emittedpower, the duration of each shot, and the interval between shots. Theassembly shown is provided with a connector 12 for receiving an opticalfiber 14 for conveying light power to an applicator 16. In addition, thehousing of the assembly 10 is provided with a connector 18 forconnection to an external control module comprising a host processor 22and an interface 20. In general an RS232 serial link is used. This linkenables the processor 22 to control the power and the duration of the oreach pulse. The or each shot can be triggered by an operator, e.g. usinga foot control. In the frequent circumstance where pulse power isdetermined by a voltage control, the control voltage can be generated bythe interface 20.

It is possible in particular for the laser used to be the apparatus soldunder the reference OPC-H005-FCTS which enables light output power to beadjusted over the range 0 to 5 W in steps of 0.1 W, which enables pulsewidth to be adjusted over the range 200 microseconds (μs) to 100 s, andwhich enables the spacing between pulses to be adjusted over the range200 μs to 100 s, with output at a wavelength of 808 nm.

The program for varying power output and pulse duration as a function ofelapsed time is loaded into the processor 22. This program can make useof a table matching duration and pulse power with time elapsed since aninitialization instant which corresponds to ICG being injected. Theprogram can also be designed to calculate a polynomial function whosecoefficients are loaded initially, with power duration then beingcalculated in real time each time a pulse is triggered.

By way of example, FIG. 2 shows theoretical variation to be given toflux density as a function of the time that has elapsed since injection,for a time constant τ of 4.8 min, after injecting a dose of 15 mg/kg ofICG, and for maximum flux density at the end of photocoagulation of 300J/cm². An increase in dose of ICG would make it possible to increase theduration during which reinforced photocoagulation can be obtained.

For the relationship giving variation of the term y=e^(−t/τ), it ispossible in particular to select the following relationship:

Time (min) y = exp (−x/4.8) or y = exp (−0.2083x) 0 1.000 0.33 0.934 0.50.901 0.66 0.872 1 0.812 1.5 0.732 2 0.659 2.5 0.594 3 0.535 4 0.435 50.353 6 0.287 7 0.233 8 0.189 9 0.153 10 0.125

As mentioned above, the exponential can be simulated by a polynomialformula. The table below gives both a first degree polynomial and asecond degree polynomial. It can be seen that the simple or first degreepolynomial suffices to reduce error relative to the exponential to lessthan 10% as from 0.33 min to beyond 9 min. A second degree polynomialenables error to be reduced to less than 2% over the same range. An evensmaller error could be obtained using a third degree formula.

y = y = % error 0.0086x² − % error Time −0.0886x + relative to 0.1693x +relative to (min) 0.8857 exponential 0.9789 exponential 0 0.886 11.40.979 2.1 0.33 0.856 7.7 0.924 1.0 0.5 0.841 6.0 0.896 0.5 0.66 0.8244.4 0.871 0.1 1 0.797 1.5 0.818 0.6 1.5 0.753 2.1 0.744 1.3 2 0.709 4.90.675 1.5 2.5 0.664 7.0 0.609 1.5 3 0.620 8.5 0.548 1.3 4 0.531 9.70.439 0.5 5 0.443 9.0 0.347 0.5 6 0.354 6.8 0.273 1.4 7 0.266 3.3 0.2151.7 8 0.177 1.2 0.175 1.4 9 0.088 6.5 0.152 0.2 10 0.000 12.5 0.146 2.1

In general, treatment is performed using a single pulse of duration andpower selected so that the total flux density received by the tissue isthat which is deduced from F₀ for the tissue concerned and for the timewhich has elapsed since injection. In practice, it is often necessary toselect a pulse duration having a value that corresponds to three to fivetimes the relaxation time of the vessels that are to be treated so as toallow heat to diffuse from the blood towards the vessel wall. The powerto be delivered is deduced while taking account of the size of the spotand the time that has elapsed since ICG was administered.

The method implemented can include a preliminary step of determining theexact location of the vessels to be attacked by illuminating thesetissues under low power after ICG has been administered. Fluorescencemakes it possible to determine the location of the new vessels and candefine the exact location to be given to the laser spot for coagulationpurposes.

FIG. 3 is a flow chart summarizing one possible implementation of thedevice when using a single shot. This flow chart is designed to stopshooting when the time that has elapsed since injection exceeds the fullduration of a treatment session, including the duration of the laserpulse.

In a variant embodiment of the invention, the processor 22 receives asignal representative of ICG concentration in the blood from a measuringapparatus. The measuring apparatus has a pickup 24 designed to be fixedon a finger and having a light-emitting diode (LED) 26 which emits lightin the absorption range of ICG, associated with a detector element suchas a photodiode 28. A monitor 30 generates a signal representative ofreal concentration on the basis of measured absorption. The processor 22is designed to control the energy of the treatment laser pulse by takingaccount of the signal output by the monitor, either in real time forcontrolling the dose that is to be applied, or to adjust the dose as afunction of the received signal. This disposition makes it possible,e.g. on the basis of initial calibration, to take account in particularof any deterioration that may have occurred in the patient's liverfunction.

Instead of being performed on a finger, measurement can be also beperformed on some other part of the body, e.g. on an earlobe.

The initial value F₀ of the fluence is selected in particular as afunction of the dose of ICG that is injected. This dose will generallynot exceed 1.5 mg/kg of patient body weight. F₀ is the flux densitywhich produces coagulation of the vessels to be destroyed withoutdamaging adjacent tissue at the initial concentration. In practice, itis common to use a flux density F₀ of about 20 J/cm² at maximum dosage,when treating new vessels at the back of the eye. The time at the end ofwhich laser treatment is performed is the time required for ICG toinvade the entire circulatory system after being injected intravenously.The duration of the laser emission will depend to a large extent on thelocation, the nature, and the diameter of the vessels to be treated.When treating the back of the eye, the duration is generally 10 ms toseveral tens of ms. For new vessels located in mucous membranes, theduration can be as long as 2 s, because diffusion towards adjacenttissue that is to be preserved is longer.

The applicator 16 can be placed outside the body or at the end of anendoscope when it is necessary to treat internal mucous membranes.

What is claimed is:
 1. A laser photocoagulator comprising: a laserhaving an emission wavelength lying in the absorption spectrum of ICGand provided with focusing means; and a laser power supply modulecontrolling emission by said laser and arranged for causing a meanfluence F at a focus of said focussing means to vary, starting from apredetermined initial instant, as an increasing function of time thatdoes not depart by more than 10% from an increasing mono-exponentialhaving the form F=F₀(1−e^(t/τ)) where F₀ is a predetermined value of thefluence, t is time elapsed and τ is a time constant lying in the range 3min to 5 min.
 2. A photocoagulator according to claim 1, wherein thepower supply module is programmed and controlled to cause said fluenceto vary by modifying power delivered by said laser.
 3. A photocoagulatoraccording to claim 1, wherein the power supply module is programmed andcontrolled to cause said fluence to vary by modifying a duration of apulse delivered by said laser.
 4. A photocoagulator according to claim1, further comprising an external programmed unit controlling the powersupply module.
 5. A photocoagulator according to claim 1, wherein theincreasing function is at least a second degree polynomial function. 6.A photocoagulator according to claim 1, wherein the increasing functionis a linear function that is terminated if it deviates more than 10%from the mono-exponential function.
 7. A photocoagulator according toclaim 1, wherein the emission wavelength of the laser is in a range of700 nm to 900 nm.
 8. A photocoagulator according to claim 1, wherein thepower supply module is connected to apparatus for measuring theinstantaneous concentration of ICG in the blood and designed to takeaccount of an output signal from said apparatus in order to adjust fluxdensity.
 9. A method of photocoagulating neo blood vessels of a patient,the method comprising the steps of: administering a predetermined doseof indocyanine green to a patient; and after a length of time haselapsed after administration, focusing, on the neo vessels to bephotocoagulated, a laser pulse that is controlled in such a manner thata mean fluence F of the laser pulse at the focus, varies from an initialflux density F₀ according to a law which does not depart by more than10% from a value F=F₀(1−e^(−t/τ)) where F₀ is a predetermined fluxdensity, t is time elapsed after administration of said indocyaninegreen and τ is a time constant lying in the range 3 min to 5 min.
 10. Amethod according to claim 9, wherein said predetermined flux density is20 J/cm2.